Problems in the Bioinorganic Chemistry of Molybdenum and Tungsten

这个奖项在无机，生物无机和有机化学计划支持研究教授理查德H。哈佛大学的霍尔姆说，该研究集中在钼和钨氧代转移酶和羟化酶催化的转化上。这些反应中的许多是纯氧原子（氧代）转移过程，其中氧原子被插入或去除（氧代转移酶），而其他反应在催化反应中利用金属配位的氢氧化物（羟化酶）。 含钨酶通常存在于超嗜热细菌和古生菌中。 在几乎所有的情况下，氧原子的最终来源或汇是水。 催化中心含有单核钼或钨原子结合到一个或两个pyranopterindithiolene配体。实验方法包括合成酶催化位点的低分子量类似物及其在反应性研究中的利用。该研究建立在与含有两个pyranopterindithiolene配体的酶的催化位点的类似物的合成和反应性结果的基础上，并通过原子转移还原有机S-氧化物和N-氧化物。 天然配体由合成的二硫纶代表，其在与钼或钨结合时作为烯-1，2-二硫醇盐起作用，并且紧密模拟由天然配位产生的电子环境。 提出了一种新的和可能的一般方法合成的二硫纶配合物，以检查类似的反应的酶硒酸还原酶，亚砷酸氧化酶，甲酸脱氢酶，乙炔水合酶，醛氧化酶，和一氧化碳脱氢酶。 其他系统包括转羟酶和脱氢酶。 功能类似物系统，转换基板做酶（但不一定在相同的反应速率域）与金属网站的酶和酶的几何和电子结构提供密切的方法，是这项研究的重点。钼和钨酶参与全球循环，它们处理碳，氮，硫，砷和硒。 某些酶，如亚硫酸盐和黄嘌呤氧化酶，存在于人体中;它们的功能障碍会导致重大的健康风险。例如，缺乏亚硫酸氧化酶可导致智力迟钝。 降低的生物合成吡喃并蝶呤indithiolene配体的能力将导致所有辅酶的缺陷，伴随包括神经综合征在内的疾病。拟议研究的更广泛的潜在影响来自于更好地了解各级生物钼/钨中心的结构，功能和机制，并将这些信息整合到这些元素和酶底物中所含元素的地球化学和环境循环的改进解释中。

This award in the Inorganic, Bioinorganic and Organometallic Chemistry program supports research by Professor Richard H. Holm at Harvard University that centers on transformations catalyzed by the molybdenum and tungsten oxotransferases and hydroxylases. Many of these reactions are pure oxygen atom (oxo) transfer processes, in which an oxygen atom is inserted or removed (oxotransferases) while others utilize metalcoordinated hydroxide in the catalytic reaction (hydroxylases). The tungsten-containing enzymes are usually found in hyperthermophilic bacteria and archaea. In practically all cases, the ultimate source or sink of oxygen atoms is water. The catalytic centers contain mononuclear molybdenum or tungsten atoms bound to one or two pyranopterindithiolene ligands. The experimental approach involves the synthesis of low molecular weight analogues of the catalytic sites of enzymes and their utilization in reactivity investigations. The research builds upon synthetic and reactivity results with analogues of the catalytic sites of enzymes that contain two pyranopterindithiolene ligands and reduce organic S-oxides and N-oxides by atom transfer. The natural ligand is represented by a synthetic dithiolene, which functions as an ene-1,2-dithiolate when bound to molybdenum or tungsten and closely simulates the electronic environment engendered by the native coordination. A new and possibly general method of synthesis of dithiolene complexes is proposed in order to examine analogue reactions of the enzymes selenate reductase, arsenite oxidase, formate dehydrogenase, acetylene hydratase, aldehyde oxidase, and carbon monoxide dehydrogenase. Other systems include the transhydroxylases and ethylbenzene dehydrogenase. Functional analogue systems that transform substrates as do enzymes (but not necessarily in the same reaction rate domain) with metal sites credibly similar to those of the enzymes and providing close approaches to enzyme-site geometric and electronic structures, are the focus of this research. Molybdenum and tungsten enzymes are implicated in global cycles thet process carbon, nitrogen, sulfur, arsenic, and selenium. Certain enzymes such as the sulfite and xanthine oxidases occur in humans; their malfunction leads to significant health risks. For example, the absence of sulfite oxidase can lead to mental retardation. Reduced ability to biosynthesize the pyranopterindithiolene ligand will lead to deficiencies in all molybdoenzymes with accompanying diseases including neurological syndromes. The broader potential impact of the proposed research derives from a better understanding of the structure, function, and mechanism of biological molybdenum/tungsten centers at all levels, and an integration of that information into improved interpretation of geochemical and environmental cycles of the these elements and those contained in enzymatic substrates.